Illicitly, methamphetamine may be sold either as pure dextromethamphetamine or in a racemic mixture. Both dextromethamphetamine and racemic methamphetamine are Schedule II controlled substances in the United States, and similarly the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions. Internationally, methamphetamine has been placed in Schedule II of the United NationsConvention on Psychotropic Substances treaty.[7]

Contrary to popular misconception, methamphetamine in both powder and crystal form is a hydrochloridesalt. The freebase form of methamphetamine (as well as amphetamine) is an oily liquid.[8] The misconception started with the fact that heroin and cocaine are injected or snorted as salts, but they are smoked in freebase form. See also: crack cocaine.

Medical use

In United States, Methamphetamine has been approved by the Food and Drug Administration (FDA) in treating ADHD and exogenous obesity (obesity originating from factors outside of the patient's control) in both adults and children.[13]

Methamphetamine is sold under the name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[14] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[13]

As methamphetamine is associated with a high potential for misuse, the drug is regulated under the Controlled Substances Act and is listed under Schedule II in the United States. Methamphetamine hydrochloride dispensed in the United States is required to include the following black box warning: Template:Cquote

Unlike cocaine and amphetamine, methamphetamine is directly neurotoxic to midbrain dopamine neurons.[27] Moreover, methamphetamine use is associated with an increased risk of Parkinson's disease due to the fact that uncontrolled dopamine effluxion is neurotoxic.[11][28] Long-term dopamine upregulation occurring as a result of methamphetamine abuse can also cause neurotoxicity, which is believed to be responsible for causing persisting cognitive deficits, such as memory loss, impaired attention, and decreased executive function. Similar to the neurotoxic effects on the dopamine system, methamphetamine can also result in neurotoxicity to serotonergic neurons.[29]

As a result of methamphetamine-induced neurotoxicity to dopaminergicneurons, chronic use may also lead to post acute withdrawals which persist beyond the withdrawal period for months, and even up to a year.[11] A study performed on female Japanese prison inmates suffering from methamphetamine addiction showed that 49% experienced "flashbacks" afterward and 21% experienced a psychosis resembling schizophrenia which persisted for longer than six months post-methamphetamine use; this amphetamine psychosis could be resistant to traditional treatment.[30] Other studies in Japan show that those who experience methamphetamine-induced psychosis are much more likely to experience psychotic symptoms again if they use methamphetamine. In addition to psychological harm, physical harm – primarily consisting of cardiovascular damage – may occur with chronic use or acute overdose.[12]

Tolerance

As with other amphetamines, tolerance to methamphetamine is not completely understood but is known to be sufficiently complex that it cannot be explained by any single mechanism. The extent of tolerance and the rate at which it develops vary widely between individuals, and even within one person. It is highly dependent on dosage, duration of use, and frequency of administration. Tolerance to the awakening effect of amphetamines does not readily develop, making them suitable for the treatment of narcolepsy.[31]

Short-term tolerance can be caused by depleted levels of neurotransmitters within the synaptic vesicles available for release into the synaptic cleft following subsequent reuse (tachyphylaxis). Short-term tolerance typically lasts until neurotransmitter levels are fully replenished; because of the toxic effects on dopaminergic neurons, this can be greater than 2–3 days. Prolonged overstimulation of dopamine receptors caused by methamphetamine may eventually cause the receptors to downregulate in order to compensate for increased levels of dopamine within the synaptic cleft.[32] To compensate, larger quantities of the drug are needed in order to achieve the same level of effects.

Reverse tolerance or sensitization can also occur.[31] The effect is well established, but the mechanism is not well understood.

Adverse effects

Addiction

Methamphetamine-induced hyperstimulation of pleasure pathways can lead to anhedonia months after use has been discontinued. Investigation of treatments targeting dopamine signalling such as bupropion, or psychological treatments that raise hedonic tone, such as behavioral activation therapy, have been suggested.[34]

It is shown that taking ascorbic acid prior to using methamphetamine may help reduce acute toxicity to the brain, as rats given the human equivalent of 5–10 grams of ascorbic acid 30 minutes prior to methamphetamine dosage had toxicity mediated,[35][36] yet this will likely be of little avail in solving the other serious behavioral problems associated with methamphetamine use and addiction that many users experience. Large doses of ascorbic acid also lower urinary pH, reducing methamphetamine's elimination half-life and thus decreasing the duration of its actions.[37]

To combat addiction, doctors are beginning to use other forms of stimulants such as dextroamphetamine, the dextrorotatory (right-handed) isomer of the amphetamine molecule, to break the addiction cycle in a method similar to the use of methadone in the treatment of heroin addicts. There are no publicly available drugs comparable to naloxone, which blocks opiate receptors and is therefore used in treating opiate dependence, for use with methamphetamine problems.[38] However, experiments with some monoamine reuptake inhibitors such as indatraline have been successful in blocking the action of methamphetamine.[39] There are studies indicating that fluoxetine, bupropion and imipramine may reduce craving and improve adherence to treatment.[40] Research has also suggested that modafinil can help addicts quit methamphetamine use,[41][42] as can Topiramate.[43]

Methamphetamine addiction is one of the most difficult forms of addiction to treat. Bupropion, aripiprazole, and baclofen have been employed to treat post-withdrawal cravings, although the success rate is low. Modafinil is somewhat more successful, but this is a Class IV scheduled drug. Adrafinil is the prodrug of Modafinil, being metabolized by the body to Modafinil in 45–60 minutes, and is not a controlled substance.Ibogaine has been used with success in Europe, where it is a Class I drug and available only for scientific research. Mirtazapine has been reported useful in some small-population studies.[44] Since phentermine, a substituted phenethylamine, is a constitutional isomer of methamphetamine, it has been suggested that it may be effective in treating methamphetamine addiction.Template:Mcn

Abrupt interruption of chronic methamphetamine use results in the withdrawal syndrome in almost 90% of the cases. The mental depression associated with methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.[40]

Psychosis

Abuse of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g. paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine induced psychosis[45] states that about 5-15% of users fail to recover completely.[46] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[45] An amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[47]

Meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, a condition informally known as meth mouth. According to the American Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high-calorie, carbonated beverages and bruxism (teeth grinding and clenching)". Some reports have also speculated that the caustic nature of the drug is a contributing factor. Methamphetamine also has the potential to cause excessive cigarette smoking for users already smoking. This combined with the methamphetamine can perpetuate the "meth mouth".[48][49] Similar, though far less severe, symptoms have been reported in clinical use of regular amphetamine, where effects are not exacerbated by extended periods of poor oral hygiene.[50][51]

Pregnancy and breastfeeding

Methamphetamine present in a mother's bloodstream passes through the placenta to a fetus, and is also secreted into breast milk. Infants born to methamphetamine-abusing mothers were found to have a significantly smaller gestational age-adjusted head circumference and birth weight measurements. Methamphetamine exposure was also associated with neonatal withdrawal symptoms of agitation, vomiting and tachypnea.[52] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[40]

Risk of sexually transmitted disease

Men who use methamphetamine, cocaine, MDMA, and ketamine, are twice as likely to have unprotected sex than those who do not use such drugs, according to British research.[53] Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners, according to American psychologistPerry N. Halkitis, a researcher examining methamphetamine use and sexual risk taking behaviors using data collected from community-based participants, an association more pronounced in HIV-positive participants. These findings suggest that methamphetamine use and engagement in unprotected anal intercourse are co-occurring risk behaviors, behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men.[54]

Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions. Methamphetamine may also cause sores and abrasions in the mouth via bruxism (teeth clenching and grinding) which can turn typically low-risk sex acts such as oral sex into high-risk sexual activity.[55]

As with the injection of any drug, if a group of users share a common needle, blood-borne diseases, such as HIV or hepatitis, can be transmitted. The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[56]

Methamphetamine is a potent central nervous system stimulant that affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and emotional responses associated with alertness or alarming conditions.[57] The acute physical effects of the drug closely resemble the physiological and psychological effects of an epinephrine-provoked fight-or-flight response, including increased heart rate and blood pressure, vasoconstriction (constriction of the arterial walls), bronchodilation, and hyperglycemia (increased blood sugar). Users experience an increase in focus, increased mental alertness, and the elimination of fatigue, as well as a decrease in appetite. It is known to produce central effects similar to the other stimulants, but at smaller doses, with fewer peripheral effects.[58] Methamphetamine's fat solubility also allows it to enter the brain faster than other stimulants, where it is more stable against degradation by monoamine oxidase (MAO).

The methyl group is responsible for the potentiation of effects as compared to the related compound amphetamine, rendering the substance more lipid-soluble, enhancing transport across the blood–brain barrier, and more stable against enzymatic degradation by monoamine oxidase (MAO). Methamphetamine causes the norepinephrine, dopamine, and serotonin (5HT) transporters to reverse their direction of flow. This inversion leads to a release of these transmitters from the vesicles to the cytoplasm and from the cytoplasm to the synapse (releasing monoamines in rats with ratios of about NE:DA = 1:2, NE: 5HT = 1:60), causing increased stimulation of post-synaptic receptors. Methamphetamine also indirectly prevents the reuptake of these neurotransmitters, causing them to remain in the synaptic cleft for a prolonged period (inhibiting monoamine reuptake in rats with ratios of about: NE:DA = 1:2.35, NE:5HT = 1:44.5).[59] Methamphetamine also interacts with TAAR1 to trigger phosphorylation of PKA and PKC, ultimately resulting in the internalization of dopamine transporters.[60] The presynaptic cell is less able to effectively remove dopamine from the synapse. The binding of methamphetamine to TAAR1 also activates adenylyl cyclase, which allows for increased intracellular cAMP.[60][61] Taken together, the binding of methamphetamine to TAAR1 results in a massive efflux of neurogenic monoamines with a sustained synaptic presence.

Methamphetamine is a potent neurotoxin, shown to cause dopaminergic degeneration.[62][63] High doses of methamphetamine produce losses in several markers of brain dopamine and serotonin neurons. Dopamine and serotonin concentrations, dopamine and 5HT uptake sites, and tyrosine and tryptophan hydroxylase activities are reduced after the administration of methamphetamine. It has been proposed that dopamine plays a role in methamphetamine-induced neurotoxicity, because experiments that reduce dopamine production or block the release of dopamine decrease the toxic effects of methamphetamine administration. When dopamine breaks down, it produces reactive oxygen species such as hydrogen peroxide.
It is likely that the approximate twelvefold increase in dopamine levels and subsequent oxidative stress that occurs after taking methamphetamine mediates its neurotoxicity.[64] The lab of David Sulzer and colleagues at Columbia University developed a technique known as "intracellular patch electrochemistry" to measure concentrations of dopamine in the cytosol,[65] and found massive increases following methamphetamine,[66] leading to the "cytosolic dopamine hypothesis" of neurotoxicity, in which dopamine oxidation, particularly close to synaptic vesicles, produce oxidative stress that in turn leads to exacerbation of autophagy that can destroy axons and dendrites.[67]

It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[74]

Pharmacokinetics

Following oral administration, methamphetamine is readily absorbed into the bloodstream, with peak plasma concentrations achieved in approximately 3.13 to 6.3 hours post ingestion. The amphetamine metabolite peaks at 10 to 24 hours. Methamphetamine is also well absorbed following inhalation and following intranasal administration.[57] It is distributed to most parts of the body. Methamphetamine is known to produce central effects similar to the other stimulants, but at smaller doses, with fewer peripheral effects.[58] Methamphetamine's high lipophilicity also allows it to cross the blood brain barrier faster than other stimulants, where it is more stable against degradation by monoamine oxidase (MAO).[57]

Methamphetamine is metabolized in the liver with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine (pholedrine); other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine.[57][75][76] Other drugs metabolized to amphetamine and methamphetamine include benzphetamine, furfenorex, and famprofazone.[77][78]Selegiline (marketed as Deprenyl, EMSAM, and others) is metabolized into levomethamphetamine which in turn is metabolized into levoamphetamine.[57][2] Although only the D-Isomer of selegiline will metabolize into active metabolites, both isomers may cause a positive result for methamphetamine and amphetamine on a drug test, in certain cases.[79]

It is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. Following an intravenous dose, 45% is excreted as unchanged parent drug and 7% amphetamine.[80] The half-life of methamphetamine is variable with a mean value of between 9 and 12 hours.[57]

Detection in biological fluids

Methamphetamine and amphetamine are often measured in urine, sweat or saliva as part of a drug-abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Chiral techniques may be employed to help distinguish the source of the drug, whether obtained legally (via prescription) or illicitly, or possibly as a result of formation from a prodrug such as famprofazone or selegiline. Chiral separation is needed to assess the possible contribution of l-methamphetamine (Vicks Inhaler) toward a positive test result.[81][82][83] In 2011, researchers at John Jay College of Criminal Justice reported that dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine. Similar claims have been made in web forums on that topic.[84]

Illicit production of methamphetamine

Synthesis

Methamphetamine is most structurally similar to methcathinone and amphetamine. Synthesis is relatively simple, but entails risk with flammable and corrosive chemicals, particularly the solvents used in extraction and purification. The six major routes of production begin with either phenyl-2-propanone (P2P) or with one of the isomeric compounds pseudoephedrine and ephedrine.[85]

Illicit methamphetamine is more commonly made by the reduction of ephedrine or pseudoephedrine, which produces the more active d-methamphetamine isomer. The maximum conversion rate for ephedrine and pseudoephedrine is 92%, although typically, illicit methamphetamine laboratories convert at a rate of 50% to 75%.[93] Most methods of illicit production involve protonation of the hydroxyl group on the ephedrine or pseudoephedrine molecule.

Though dating back to the discovery of the drug, the Nagai route[94] did not become popular among illicit manufacturers until ca. 1982, and comprised 20% of production in Michigan in 2002[95] It involves red phosphorus and hydrogen iodide (also known as hydroiodic acid or iohydroic acid). (The hydrogen iodide is replaced by iodine and water in the "Moscow route"[96]) The hydrogen iodide is used to reduce either ephedrine or pseudoephedrine to methamphetamine.[91] On heating the precursor is rapidly iodinated by the hydrogen iodide to form iodoephedrine. The phosphorus assists in the second step, by consuming iodine to form phosphorus triiodide (which decomposes in water to phosphorous acid, regenerating hydrogen iodide). Because hydrogen iodide exists in a chemical equilibrium with iodine and hydrogen, the phosphorus reaction shifts the balance toward hydrogen production when iodine is consumed.[97] In Australia, criminal groups have been known to substitute "red" phosphorus with either hypophosphorous acid or phosphorous acid (the "Hypo route").[96][98][99] This is a hazardous process for amateur chemists because phosphine gas, a side-product from in situ hydrogen iodide production,[100] is extremely toxic to inhale. The reaction can also create toxic, flammable white phosphorus waste.[91] Methamphetamine produced in this way is usually more than 95% pure.[101]

The Birch reduction, also called the "Nazi method", became popular in the mid-to-late 1990s and comprised the bulk of methamphetamine production in Michigan in 2002.[95] It reacts pseudoephedrine with liquid anhydrous ammonia and an alkali metal such as sodium or lithium. The reaction is allowed to stand until the ammonia evaporates.[103] However, the Birch reduction is dangerous because the alkali metal and ammonia are both extremely reactive, and the temperature of liquid ammonia makes it susceptible to explosive boiling when reactants are added. It has been the most popular method in Midwestern states of the U. S. because of the ready availability of liquid ammonia fertilizer in farming regions.[91][104]

In recent years, a simplified "Shake 'n Bake" one-pot synthesis has become more popular. The method is suitable for such small batches that pseudoephedrine restrictions are less effective, it uses chemicals that are easier to obtain (though no less dangerous than traditional methods), and it is so easy to carry out that some addicts have made the drug while driving.[105] It involves placing crushed pseudoephedrine tablets into a nonpressurized container containing ammonium nitrate, water, and a hydrophobic solvent such as Coleman fuel[106] or automotive starting fluid, to which lye and lithium (from lithium batteries) is added. Hydrogen chloride gas produced by a reaction of salt with sulfuric acid is then used to recover crystals for purification. The container needs to be "burped" periodically to prevent failure under accumulating pressure, as exposure of the lithium to the air can spark a flash fire. The battery lithium can react with water to shatter a container and potentially start a fire or explosion.[106] This mode of synthesis is particularly notorious for causing burns and overwhelming burn wards.

Production and distribution

Until the early 1990s, methamphetamine for the U.S. market was made mostly in labs run by drug traffickers in Mexico and California. Indianastate police found 1,260 labs in 2003, compared to just 6 in 1995, although this may be partly a result of increased police activity.[107] As of 2007, drug and lab seizure data suggests that approximately 80 percent of the methamphetamine used in the United States originates from larger laboratories operated by Mexican-based syndicates on both sides of the border and that approximately 20 percent comes from small toxic labs (STLs) in the United States.[108]

Mobile and motel-based methamphetamine labs have caught the attention of both the U.S. news media and the police. Such labs can cause explosions[109] and fires and expose the public to hazardous chemicals. Those who manufacture methamphetamine are often harmed by toxic gases. Many police departments have specialized task forces with training to respond to cases of methamphetamine production. The National Drug Threat Assessment 2006, produced by the Department of Justice, found "decreased domestic methamphetamine production in both small and large-scale laboratories", but also that "decreases in domestic methamphetamine production have been offset by increased production in Mexico." The report concluded that "methamphetamine availability is not likely to decline in the near term. "[110]

Methamphetamine labs can give off noxious fumes, such as phosphine gas, methylamine gas, solvent vapors, acetone or chloroform, iodine vapors, white phosphorus, anhydrous ammonia, hydrogen chloride/muriatic acid, hydrogen iodide, lithium and sodium gases, ether, or methamphetamine vapors.[95] If performed by amateurs, manufacturing methamphetamine can be extremely dangerous. If the red phosphorus overheats, because of a lack of ventilation, phosphine gas can be produced. This gas is highly toxic and, if present in large quantities, is likely to explode upon autoignition from diphosphine, which is formed by overheating phosphorus.

In July 2007, Mexican officials at the port of Lázaro Cárdenas seized a ship carrying 19 tons of pseudoephedrine, a raw material needed for methamphetamine.[111] The shipment originated in Hong Kong and passed through the United States at the port of Long Beach prior to its arrival in Mexico.

The Australian Crime Commission's illicit drug data report for 2011–2012 was released in western Sydney, Australia on 20 May 2013 and revealed that the average strength of crystal methamphetamine doubled in most Australian jurisdictions within a 12-month period and the majority of domestic laboratory closures involved small "addict-based" operations.[112]

Impurities and adulterants

In Japan, methamphetamine seizures are usually white crystals of high purity, but contain impurities that vary according to the means of production, and are sometimes adulterated.

Diagnostic impurities are the naphthalenes 1-benzyl-methylnaphthalene and 1,3-dimethyl-2-phenylnaphthalene,[97] arising in the Nagai and Leuckart routes, and cis- or trans- 1,2-dimethyl-3-phenylaziridine, ephedrine, or erythro-3,4-dimethyl-
5-phenyloxazolidine, arising in the Nagai and Emde routes; these are absent in the reductive amination route.[88] Characteristic impurities of the Birch route include N-methyl-1-(1-(1,4-cyclohexadienyl))-2-propanamine.[103] Methamphetamine produced by the Birch route contains phenyl-2-propanone, the precursor for the reductive amination route, as a degradation product.[97] However, specific diagnostic impurities are not very reliable in practice, and it is generally preferable for forensic technicians to evaluate a larger profile of trace compounds.[85]

In the United States, illicit methamphetamine comes in a variety of forms with prices varying widely over time.[113] Most commonly, it is found as a colorless crystalline solid. Impurities may result in a brownish or tan color. Colorful flavored pills containing methamphetamine and caffeine are known as yaa baa (Thai for "crazy medicine").

An impure form of methamphetamine is sold as a crumbly brown or off-white rock, commonly referred to as "peanut butter crank".[114] It may be diluted or cut with non-psychoactive substances like inositol, isopropylbenzylamine or dimethylsulfone. Another popular method is to combine methamphetamine with other stimulant substances, such as caffeine or cathine, into a pill known as a "Kamikaze", which can be particularly dangerous due to the synergistic effects of multiple stimulants. Reports in 2007 of the appearance of flavored "Strawberry Quik meth" circulated in the media and local law enforcement,[115] but were debunked in 2010 by the DEA, although meth of varying colors has been seized.[116]

Rarely, the impure reaction mixture from the hydrogen iodide/red phosphorus route is used without further modification, usually by injection; it is called "ox blood".[103] "Meth oil" refers to the crude methamphetamine base produced by several synthesis procedures. Ordinarily it is purified by exposure to hydrogen chloride, as a solution or as a bubbled gas, and extraction of the resulting salt occurs by precipitation and/or recrystallization with ether/acetone.[103]

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